Therapeutic swabs for treating upper respiratory infections

ABSTRACT

Compounds and methods for preventing or treating upper respiratory virus infections in humans and animal species are disclosed. The compounds may exhibit antimicrobial, antiviral, anti-inflammatory, anticoagulant or cytoprotective activities. The methods may deliver compounds to be delivered to the nasal and oral cavities, nasopharynx, and posterior pharynx, the primary sites of upper respiratory infections, such as influenza, SARS, and SARS-CoV-2. Therapeutic swabs comprising one or more compounds are may be used to deliver one or more compounds to deliver the above primary sites of the individuals infected with one or more upper respiratory viruses or other pathogens.

BACKGROUND OF THE INVENTION

Infections caused by upper respiratory pathogens, including the mostdangerous novel class of COVID-19-causing coronavirus SARS-CoV-2 and itsmutant variant strains, transmissible in close proximity, triggeringrespiratory illnesses and serious health complications, are responsiblefor a large number of hospitalizations and deaths every year and presenta significant threat to the human health (Satia, et al. PLOS ONE. 15: e0228544 (2020); Lai et al. Int. J. Antimicrob. Agents. 55:10593 (2020);Nakamichi et al. Scientific Reports. 11:4802 (2021). As of Aug. 30,2021, according to the World Health Organization, COVID-19 has affectednearly 216 million individuals worldwide claiming more than 4.5 millionlives with 38.5 million infections and in excess of 631,000 deaths inthe United States (World Health Organization Dashboard: Aug. 30, 2021).These numbers are increasing daily at an alarming rate.

Rapid mutational changes in SARS-CoV-2 resulting in new highlycontagious and more deadly variants have worsened the pandemic, posingdifficult challenges to effective treatment (Volz et al. Cell. 184:64-75(2021); Korber et al. Cell. 184:64-75 (2021); Davies et al. Science.372: eabg3055 (2021)). Although vaccines are reportedly effective inreducing the severity of COVID-19 illnesses, hospitalizations, anddeaths, none is yet known to prevent infections or reinfections of thevaccinated individuals by rapidly emerging highly contagious and moredeadly mutant viral variants. In addition, children, older population,and individuals with underlying health conditions, all are at asignificantly higher risk of acquiring the infection and developinghyperinflammatory syndrome and other severe health complications(Toniati et al. Autoimmun. Rev. 19:102568 (2020); Gustine, J. N. &Jones, D. Am. J. Pathol. 191:4-17 (2021); Nikolich-Zugich et al.GeroScience. 342:505-514 (2020); CDC, August 2021)). Therapeutic optionsfor treating COVID-19 patients are limited and require hospitalizations.

The dire COVID-19 pandemic situation calls for an urgent need for safeand effective therapeutics along with convenient, preferablyself-administering approaches, to treat the infected individuals at theearly symptomatic stage of infection. It is critical for our own safetyand also for minimizing the spread of the disease to others.

Highlights of the Invention

-   -   The present invention offers the first multifactorial        therapeutic approach designed for specific and direct targeting        the sites of upper respiratory infections.    -   The Therapeutic Swabs offers an innovative therapeutic device        system designed to: (a) accommodate a plurality of unique        combination of drugs exhibiting antiviral activity,        antimicrobial activity, and other crucial innate host protective        functions; and (b) deliver them simultaneously and specifically        to the nasal cavity, nasopharynx, and posterior pharynx, the        primary sites of upper respiratory infections.    -   This invention presents the first configuration design        consisting of plurality of drugs possessing distinct functions,        such as: (a) antiviral and antimicrobial activities to disrupt        the pathogens and inhibit their replication; (b) induce strong        innate cytoprotective response to prevent virus-induced cell        death; (c) anti-inflammatory activity to reduce inflammation        associated with upper respiratory infections; and (d) partial        anticoagulant activity to reduce the possibility of blood        clotting reported in COVID-19 patients—all to collectively        combat infections and provide an effective host protection.    -   The therapeutic approach presented in this invention is pivotal        for our first defense against upper respiratory infections. It        has a tremendous potential for its utility on a mass-scale to        help control the currently out-of-control COVID-19 pandemic        situation, and also as a safeguard for future viral outbreaks.

SUMMARY OF THE INVENTION

This invention addresses the critical and unmet needs related to upperrespiratory infections—one of which is caused by the most prevalent,highly contagious, and deadly novel coronavirus SARS-CoV-2. It is ofenormous global public health concern. Accordingly, the presentinvention relates to the first one-of-its-kind therapeutic approachconsisting of multifunctional drugs intended for their direct deliveryto the nasal cavity, nasopharynx, and posterior pharynx, the primarysites of upper respiratory infection, by means of drug-adsorbed ordrug-conjugated Therapeutic Swabs device system. Since epithelial cellsare the primary initial target site of upper respiratory infections,delivery of the drugs exhibiting various crucial biological functionsdirectly to the sites of infection, presents this invention as a novelmultifactorial therapeutic approach. This invention offers a convenient,efficient, specific and rapid drug application on a mass-scalepresenting Therapeutic Swabs device system as an ideal therapeuticmodality to treat the infected individuals and to effectively controlthe current out-of-control deadly COVID-19 pandemic and otherrespiratory infections.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrating the configuration of the therapeutic swabs devicesystem comprising unique selection of drugs exhibiting crucial multiplefunctions depicted as [C], [D], [E] and [F] mounted on a straight stem.

FIG. 2 illustrating the configuration of the therapeutic swabs devicesystem comprising unique selection of drugs exhibiting crucial multiplefunctions depicted as [C], [D], [E] and [F] mounted on a curved orflexible stem.

Wherein:

[A] is stem made from materials meeting requirements for general safety,preferably using biodegradable materials. The curved or flexible stemshown in FIG. 2 is designed for easy access to the nasal and oralcavities in the humans and in animals;

[B] represents drug-adsorbed or drug-conjugated swabs attached on bothends of the stem [A]. If desired, only one swab on the stem of theTherapeutic Swabs may be used;

The dimensional specifications (e.g., size, appearance, materialdensity, and physical or chemical composition) for “stem” [A] and“swabs” [B] used in the Therapeutic Swabs device system are notexplicitly defined; rather, these are to be designed for drug deliveryin the humans and in animals based on the anatomy of their nasal andoral cavities;

The compound [C] is an antimicrobial and antiviral agent (e.g.,antibiotics, proteins, peptides, peptidomimetics, brilacidin,antibodies, etc.) with brilacidin as an example, wherein the saidcompound is the same drug attached, adsorbed or chemically conjugatedand used in the configuration of the present invention;

The compound [C] is a different antimicrobial and antiviral drug,attached, adsorbed or chemically conjugated and used in theconfiguration of the present invention;

The compound [C] is absent from the configuration of the presentinvention;

The compound [D] is hemin, a strong inducer of an endogenouscytoprotective enzyme heme oxygenase-1 (HO-1), wherein the said compoundis the same drug attached, adsorbed or chemically conjugated and used inthe configuration of the present invention;

The compound [D] is a different inducer of HO-1, wherein the saidcompound is a different drug attached, adsorbed or chemically conjugatedand used in the configuration of the present invention;

The compound [D] is inducer of HO-1 via upstream transcription factorNrf2, including but not limited to, 4-octyl-itaconate and dimethylfumarate, wherein the compound is adsorbed or chemically conjugated andused in the configuration of the present invention;

The compound [D] is absent from the configuration of the presentinvention; The compound [E] is low molecular weight heparin (LMWH),anticoagulants, low- or non-anticoagulant heparin, and other modifiedglycosaminoglycans (GAG) derivatives, including heparin, wherein thesaid compound is the same drug attached, adsorbed or chemicallyconjugated and used in the configuration of the present invention;

The compound [E] is a different LMWH, anticoagulants, low- ornon-anticoagulant heparin, and other modified GAG derivatives, includingheparin, wherein the said compound is different drug attached, adsorbedor chemically conjugated and used in the configuration of the presentinvention;

The compound [E] is a different compound possessing a net negativelycharge attached, adsorbed or chemically conjugated and used in theconfiguration of the present invention;

The compound [E] is absent from the configuration of the presentinvention;

The “Other drug formulations” [F] is a drug, drug components, or drugcombinations exhibiting antiviral, antimicrobial, cytoprotective,anti-inflammatory, and anticoagulant activities used in theconfiguration of the present invention;

The “Other drug formulations” [F] is a drug or drug componentsexhibiting antiviral activity, including but not limited to, remdesivir,favipiravir, polyclonal or monoclonal antibodies, proteins, peptides,peptidomimetics, nucleotides, etc., either individually or in anypreferred combinations used in the configuration of the presentinvention;

The “Other drug formulations” [F] is a drug, drug components, or drugcombinations exhibiting anti-inflammatory activity, including but notlimited to, corticosteroids, indomethacin, other nonsteroidalanti-inflammatory drugs (NSAIDs), etc., used in the configuration of thepresent invention;

The compound [F] is absent from the configuration of the presentinvention.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Respiratory pathogens are known to primarily target the lung (Subbarao,K. & Mahanty, S. Immunity. 52:905-909 (2020)). These pathogens enterthrough the nasal or oral cavity. Therefore, it is desirable to targetthe nasal cavity, oral cavity, nasopharynx, and posterior pharynxdirectly where the primary infections occur to provide rapid and robustprotection.

This invention relates to a therapeutic swabs device system comprisingplurality of drugs possessing various crucial cellular protectivefunctions (e.g., antiviral, antimicrobial, cytoprotective, andanti-inflammatory) intended to specifically and directly targeting theprimary sites of upper respiratory infections. The approach presented inthis invention not only has the potential to effectively treat upperrespiratory infections, it can also reduce the risk of adverse sideeffects associated with high systemic absorption of drugs that areadministered in the form of oral medicines or injections. Themultifactorial generic antiviral therapeutic approach presented in thisinvention is much-warranted to control the current out-of-controlCOVID-19 pandemic situation.

As will be familiar to those skilled in the art, systemic administrationof drugs either orally, by injections, or via other routes is notwithout the risk of causing adverse effects, sometimes serious innature. The preferred embodiment of the present invention contemplatesto Therapeutic Swabs device system as a therapeutic device fordelivering plurality of drugs exhibiting distinct antiviral,antimicrobial and cytoprotective functions for specifically targetingthe nasal cavity, nasopharynx, and throat, the primary sites of upperrespiratory infections.

It will be appreciated that one or more crucial drugs are deliveredsimultaneously and directly to the infected sites of upper respiratoryinfections for maximizing their effectiveness, signifying a broaderpublic health utility of the present invention. Accordingly, anembodiment of the present invention relates to selection of plurality ofdrugs possessing: (a) antiviral activity to disrupt the viruses orinhibit viral replication; (b) anti-inflammatory activity to reduceinflammation associated with viral infections; (c) cytoprotectivefunction to prevent virus-induced cell death; (d) anticoagulant activityto reduce blood clotting in upper respiratory viral infections; and (e)bearing the net negatively charged moieties on one or more drugs topotentially bind the positively charged viruses and, as a result,protect the target cells from being infected.

The term “antiviral/antimicrobial drugs” used herein (e.g., antiviral,antimicrobial, antibiotics, proteins, peptides, peptidomimetics,antibodies, nucleotides, etc.), depicted as [C] in FIG. 1 and FIG. 2 ofthis invention, signifies drugs or compounds, synthetic or naturalproducts, exhibiting antiviral or antimicrobial activity. An embodimentof the present invention relates to utility of brilacidin, a peptide ora biomimetic antimicrobial polymer derived from a host protein defensinexhibiting antiviral and antibacterial activities (Tew et al. Proc.Natl. Acad. Sci. 99:5110-5114 (2002); Ding, J., Chou, Y. Y. & Chang, T.L. J. Innate Immunity. 1:413-420 (2009); Som et al. Clin. VaccineImmunol. 19:1784-1791 (2012); Brice, D. C. & Diamond, G. Curr. Med.Chem. 27:1420-1443 (2020); Di, Y. P. Curr. Med. Chem. 27:1385-1386(2020); Bakovic et al. Viruses. 13:271, (2021)), depicted as [C] in FIG.1 and FIG. 2 , in the configuration of the present invention. Brilacidinmay be substituted with other drugs or agents exhibiting antimicrobialcharacteristics.

An embodiment of the present invention specifically utilizes hemeoxygenase-1 (HO-1)-inducing drugs, depicted as [D], providing a strong“generic innate cellular protection” against a wide variety ofinfections, regardless of types, mutants, or strains of the pathogens,such as HIV-1, Ebola virus, Vaccinia virus, Zika virus, West Nile virus,Dengue virus, even a parasite Leishmania donovani, and, more recently, amycoplasma Mycoplasma hyorhinis (Devadas, K. & Dhawan, S. J. Immunol.176:4252-4257 (2006); Zhou et al. Curr. Trends Immunol. 14:53-56 (2013);Dhawan, S. Curr. Trends Immunol. 14:65-70 (2013); Meseda et al. Biochem.Biophys. Res. Commun. 454:84-88 (2014); Huang et al. Curr. TrendsImmunol. 17:117-123 (2016); Hill-Batorski et al. J. Virol.87:13795-13802 (2013); Huang et al. Virology. 503: 1-5 (2017); Chi etal. J. Transl. Med. 14:35 (2016); Wagener et al. Antioxidants. 9:540(2020); Chi et al. J. Transl. Med. 14:35 (2016); Rossi et al. Med.Hypothesis. 144:110242 (2020); Huang et al. FEBS Open Bio. Publishedonline on Aug. 10, 2021; https://doi.org/10.1002/2211-5463.13271;Dhawan, S. Curr. Trends Immunol. 22:19-21 (2021); Dhawan, S. Curr.Trends Immunol. 22:43-47 (2021); Dhawan, S. Am. Pharm. Rev. 48-49(May/June 2021)). Therefore, the utility of HO-1 inducers in theconfiguration of this invention presents a significant advancement forthe general host protection against infections.

It will be appreciated that hemin, depicted as [D] in FIG. 1 and FIG. 2of this invention, is the active component of a previously FDA-approveddrug Panhematin® for another indication (Siegert, S. W. & Holt, R. J.Adv. Ther. 9:842-857 (2008); therefore, this highly significantadvantage rules out any serious adverse side effects of this drug thatinduces strong innate cytoprotective, anti-inflammatory, and antiviralfunctions.

The term “HO-1 inducer”, including Nrf2-dependent (or independent) HO-1inducers, depicted as [D] in FIG. 1 and FIG. 2 of this invention,signifies the agents exhibiting potent cytoprotective activity againstinfections that are much-needed to effectively combating and forinducing a robust innate host defense against deadly infections.

The drugs depicted as [C] and [D] in FIG. 1 and FIG. 2 of thisinvention, may be substituted with other drugs or agents exhibitingsimilar functional characteristics.

A rare blood clotting in certain COVID-19-vaccinated individuals isreported (Ledford, H. Nature 596:479-481 (2021). Whereas heparin isthought to be linked to blood clotting (cited in the above reference),non-anticoagulant heparin derivative, the low molecular weight heparin(LMWH), has been reported to elicit beneficial effects on mortality inCOVID-19 by: (a) inhibition of heparinase activity; (b) reduction ofchemokines and cytokines; (c) interference with leukocyte trafficking;and (d) reducing viral cellular entry (Buijsers et al. EBioMedicine.59:102969 (2020).

Accordingly, an embodiment of the present invention is anticoagulants orlow-anticoagulants, e.g., chondroitin sulfate (CS), LMWH, or modifiedlow- or non-anticoagulant glycosaminoglycans (GAG) derivatives,including N-acetylated glycol-split heparin, and other heparinmodifications, depicted as [E] in FIG. 1 and FIG. 2 , providing abeneficial utility of non-anticoagulant activity or reducedanticoagulant activity in the configuration of the present inventionwithout unwanted side effects (Duckworth et al. Oncotarget.6:23671-23687 (2015); Casu, B., Vlodaysky, I & Sanderson, R. D.Pathophysiol. Haemost. Thromb. 36:195-203 (2009).

CS is a small molecule with molecular mass of ˜463 Da as compared toheterogeneous heparin with high molecular mass ranging between 3,000 Dato 30,000 Da. Therefore, CS, LMWH or other modified GAG derivativespresent better and useful alternatives for use in the configuration ofthis invention. In addition, the net negative charge on CS, LMWH ormodified GAGs could potentially bind positively charged upperrespiratory viruses, including SARS-CoV-2, to prevent their attachmentto the target cells.

The low- or non-anticoagulant heparin, LMWH, or modified GAGderivatives, including heparin, depicted as compound [E] in FIG. 1 andFIG. 2 , may be used or replaced by other independent drug moleculespossessing net negatively charged moieties.

The term “Other drug formulations” (shown as [F] in FIG. 1 and FIG. 2 )used herein refers to drugs or drug components exhibiting antiviral,antimicrobial, anti-inflammatory, anticoagulant, cytoprotective, andother relevant crucial medicinal functions.

Therapeutic Swabs device system presents a significant advantage overconventional administration of antiviral and antimicrobial drugs fortreating upper respiratory infections via other routes (e.g., pills,capsules, via injections, etc.) in terms of minimizing high systemicabsorption of the drugs. This invention also presents much superiorityover the antiviral and antimicrobial drug administration by nasal dropsor nasal sprays in terms of minimizing the dripping or spilling of thedrugs and/or contaminated nasal secretions. Collectively, this inventionpresents a novel configuration designed for an effective therapeuticapproach for targeting specifically the infected sites of upperrespiratory infections enabling a broadly applicable remedy for treatingupper respiratory infections in the humans and in animals.

The utility of the present invention will have a tremendous positiveimpact on the public health safety on a mass-scale in controlling thecurrent COVID-19 pandemic crisis as well as in preparing us for theunforeseen future viral outbreaks. The Therapeutic Swabs device systempresents a convenient and useful therapeutic tool to offer medicalintervention by healthcare professionals, by other individuals, byfriends and family members, by self-administration, and for home use tominimize the spread of deadly respiratory infections to others and toretard the disease progression.

1-3. (canceled)
 4. A therapeutic swab device consisting of: a stemhaving a first end and a second end; a first drug-loaded swab located atthe first end, the first drug-loaded swab consisting of a swab and afirst plurality of drugs consisting of a first composition consistingof: at least one antiviral agent, at least one heme oxygenase-1 (HO-1)inducer selected from the group consisting of hemin, 4-octyl-itaconate,dimethyl fumarate, and combinations thereof, an anticoagulant selectedfrom a modified heparin, a low molecular weight heparin (LMWH),chondroitin sulfate (CS), and a modified glycosaminoglycans (GAG), and adrug component having anti-inflammatory activity; and a seconddrug-loaded swab located at the second end, wherein the seconddrug-loaded swab consists of a second plurality of drugs identical tothe first composition, wherein the therapeutic swab is configured foruse in a nasopharynx and a posterior pharynx of a subject.
 5. (canceled)6. (canceled)
 7. The therapeutic swab of claim 4, wherein the stem isrigid.
 8. The therapeutic swab of claim 4, wherein the stem is flexible.9. The therapeutic swab of claim 4, wherein the antiviral agent is aprotein.
 10. The therapeutic swab of claim 4, wherein the antiviralagent is a peptide.
 11. The therapeutic swab of claim 4, wherein theantiviral agent is a peptidomimetic.
 12. The therapeutic swab of claim4, wherein the antiviral agent is an antibody.
 13. The therapeutic swabof claim 4, wherein the anticoagulant is a modified heparin.
 14. Thetherapeutic swab of claim 4, wherein the anticoagulant is LMWH.
 15. Thetherapeutic swab of claim 4, wherein the anticoagulant is CS.
 16. Thetherapeutic swab of claim 4, wherein the anticoagulant is GAG.
 17. Atherapeutic swab device for treating an upper respiratory infection in asubject, the therapeutic swab comprising: a stem having a first end anda second end; a first drug-loaded swab located at the first end, thefirst drug-loaded swab consisting of a swab and a first plurality ofdrugs consisting of: brilacidin, at least one innate heme oxygenase-1(HO-1) inducing agent selected from hemin, 4-octyl-itaconate, dimethylfumarate, and combinations thereof, at least one anticoagulant selectedfrom a modified heparin, a low molecular weight heparin (LMWH),chondroitin sulfate (CS), and a modified glycosaminoglycans (GAG), andat least one drug component having anti-inflammatory activity, whereinthe therapeutic swab is configured for use in a nasopharynx and aposterior pharynx of a subject.
 18. The therapeutic swab of claim 17further comprising a second drug-loaded swab located at the second end.19. The therapeutic swab of claim 18, wherein the second drug-loadedswab includes a second plurality of drugs having a composition identicalto the first plurality of drugs.
 20. (canceled)
 21. The therapeutic swabof claim 17, wherein the stem is rigid.
 22. The therapeutic swab ofclaim 17, wherein the stem is flexible.
 23. A method of treating anupper respiratory infection in a human subject, the method comprising:locally administering a plurality of drugs located on a drug-loaded swabto at least one body region of the subject, the at least one body regionincluding the posterior pharynx of the human subject, and the pluralityof drugs consisting of: at least one antiviral agent, hemin, ananticoagulant selected from a modified heparin, a low molecular weightheparin (LMWH), chondroitin sulfate (CS), and a modifiedglycosaminoglycans (GAG), and a drug component having anti-inflammatoryactivity.
 24. The method of claim 23, further comprising locallyadministering the plurality of drugs located on both ends of adouble-ended drug-loaded swab to the nasal cavities, oral cavities, andnasopharynx of a subject.
 25. The method of claim 23, further comprisinglocally administering the plurality of drugs located on both ends of adouble-ended drug-loaded swab to the nasal cavities, oral cavities, ornasopharynx of the subject.
 26. The therapeutic swab of claim 4, whereinthe heme oxygenase-1 (HO-1) inducer is hemin, 4-octyl-itaconate, ordimethyl fumarate.
 27. The therapeutic swab of claim 4, wherein the hemeoxygenase-1 (HO-1) inducer is dimethyl fumarate.
 28. The therapeuticswab of claim 4, wherein the heme oxygenase-1 (HO-1) inducer is4-octyl-itaconate.
 29. The therapeutic swab of claim 4, wherein the hemeoxygenase-1 (HO-1) inducer is hemin.